Aug 2026· Medical Oncology· Vol 43· 0 citations· 101 references
Medicine
TL;DR
This review outlines the molecular mechanisms driving neoantigen generation in CRC, including frameshift mutations, single-nucleotide variants, alternative RNA splicing, and circular RNA-derived epitopes, and evaluates neoantigen-directed therapeutic platforms, encompassing personalized neoantigen vaccines and adoptive T-cell therapies that are engineered to recognize neoantigen-derived epitopes.
Immunotherapy has reshaped the treatment landscape of colorectal cancer (CRC), with the clearest and most durable benefit established in mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) disease. However, framing CRC immunotherapy simply as "MSI-H responsive versus microsatellite stable (MSS) resistant" is no longer sufficient. Recent studies indicate that a subset of proficient mismatch repair (pMMR) colon cancers, particularly in the neoadjuvant setting, can mount clinically meaningful responses to immune checkpoint blockade, suggesting that disease stage, local immune organization, and treatment timing critically influence immunotherapy sensitivity. In parallel, emerging evidence has expanded the relevant immune landscape beyond the tumor bed itself, showing that spatially organized stromal and adipose niches can actively divert tumor-reactive lymphocytes and promote immune escape. These advances shift the central challenge in CRC immunotherapy from simply identifying new agents to defining when and in whom immune resistance is reversible, and which biological bottlenecks-such as vascular dysfunction, myeloid suppression, and spatial immune exclusion-must be overcome. In this context, alternative checkpoint inhibitors, bispecific antibodies, cellular therapies, vaccines, nanotechnology-enabled platforms, and microbiome-targeted approaches remain important, but their translational maturity and evidentiary support differ substantially. Biomarker development is likewise evolving from static genomic classification toward dynamic and mechanism-informed stratification incorporating circulating tumor DNA (ctDNA), chromosomal instability, immune architecture, and treatment-induced response trajectories. This review synthesizes recent advances in CRC immunotherapy while emphasizing evidence hierarchy, biomarker-guided patient selection, and the mechanistic basis of combination strategies. We argue that the next phase of CRC immunotherapy will depend less on the indiscriminate addition of novel agents and more on the rational deployment of immunotherapy across molecularly, spatially, and temporally defined disease states.
Recent experimental platforms have been developed to validate neoantigen immunogenicity, which can be complemented by single-cell RNA/T-cell receptor sequencing to identify tumor-reactive T cell clones.
Takamasa Ishino, Yosuke Togashi· The FEBS Journal· 0 citations
ERVs are consistently expressed and immunogenic in GBM, representing a scalable, tumor-specific antigen source that may overcome limitations of low mutational burden and provide a proof-of-concept for personalized vaccines targeting ERV-derived neoantigens.
Kenan Zhang, Megan C. Benz, K. Hotchkiss et al.· Journal of Immunology· 0 citations
This review aims to critically analyze the immunogenic and oncogenic potential of CTAs, synthesize current preclinical and clinical evidence across distinct CTA subfamilies, and highlight innovative CTA-based immunotherapeutic strategies for the treatment of melanoma.
Suzana Lemke Lanius, B. Pacheco, Fernanda Severo Sabedra Sousa et al.· Pathology, Research and Prac...· 0 citations
Overall, cancer vaccines are unlikely to become universal stand-alone treatments for advanced solid tumors, and their most credible role may emerge in molecularly selected patients, adjuvant therapy, minimal residual disease, virus-associated malignancies, and rational combinations with checkpoint inhibitors or tumor microenvironment-modulating agents.
Dario Rusciano· Frontiers in Cell and Develo...· 0 citations
